Pyrrolo [2,3-c] pyridine derivatives

ABSTRACT

The present invention relates to compounds of formula I 
                         
wherein R 1  to R 4  are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No.05112186.1, filed Dec. 15, 2005, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel5-piperazinyl-1H-pyrrolo[2,3-c]pyridine derivatives, their manufacture,pharmaceutical compositions containing them and their use asmedicaments. The active compounds of the present invention are useful intreating obesity and other disorders.

In particular, the present invention is directed to compounds of thegeneral formula

and pharmaceutically acceptable salts thereof.

The compounds of formula I are antagonists and/or inverse agonists atthe histamine 3 receptor (H3 receptor).

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND

Histamine (2-(4-imidazolyl)ethylamine) is one of the aminergicneurotransmitters which is widely distributed throughout the body, e.g.the gastrointestinal tract (Burks 1994 in Johnson L. R. ed., Physiologyof the Gastrointestinal Tract, Raven Press, NY, pp. 211-242).

Histamine regulates a variety of digestive pathophysiological eventslike gastric acid secretion, intestinal motility (Leurs et al., Br J.Pharmacol. 1991, 102, pp 179-185), vasomotor responses, intestinalinflammatory responses and allergic reactions (Raithel et al., Int.Arch. Allergy Immunol. 1995, 108, 127-133). In the mammalian brain,histamine is synthesized in histaminergic cell bodies which are foundcentrally in the tuberomammillary nucleus of the posterior basalhypothalamus. From there, the histaminergic cell bodies project tovarious brain regions (Panula et al., Proc. Natl. Acad. Sci. USA 1984,81, 2572-2576; Inagaki et al., J. Comp. Neurol 1988, 273, 283-300).

According to current knowledge, histamine mediates all its actions inboth the CNS and the periphery through four distinct histaminereceptors, the histamine H1, H2 H3 and H4 receptors.

H3 receptors are predominantly localized in the central nervous system(CNS). As an autoreceptor H3 receptors constitutively inhibit thesynthesis and secretion of histamine from histaminergic neurons (Arranget al., Nature 1983, 302, 832-837; Arrang et al., Neuroscience 1987, 23,149-157). As heteroreceptors, H3 receptors also modulate the release ofother neurotransmitters such as acetylcholine, dopamine, serotonin andnorepinephrine among others in both the central nervous system and inperipheral organs, such as lungs, cardiovascular system andgastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol. 1982,107, 919-923; Blandina et al. in The Histamine H3 Receptor (Leurs R Land Timmermann H eds, 1998, pp 27-40, Elsevier, Amsterdam, TheNetherlands). H3 receptors are constitutively active, meaning that evenwithout exogenous histamine, the receptor is tonically activated. In thecase of an inhibitory receptor such as the H3 receptor, this inherentactivity causes tonic inhibition of neurotransmitter release. Thereforeit may be important that a H3R antagonist would also have inverseagonist activity to both block exogenous histamine effects and to shiftthe receptor from its constitutively active (inhibitory) form to aneutral state.

The wide distribution of H3 receptors in the mammalian CNS indicates thephysiological role of this receptor. Therefore the therapeutic potentialas a novel drug development target in various indications has beenproposed.

The administration of H3R ligands—as antagonists, inverse agonists,agonists or partial agonists—may influence the histamine levels or thesecretion of neurotransmitters in the brain and the periphery and thusmay be useful in the treatment of several disorders. Such disordersinclude obesity, (Masaki et al; Endocrinol. 2003, 144, 2741-2748;Hancock et al., European J. of Pharmacol. 2004, 487, 183-197),cardiovascular disorders such as acute myocardial infarction, dementiaand cognitive disorders such as attention deficit hyperactivity disorder(ADHD) and Alzheimer's disease, neurological disorders such asschizophrenia, depression, epilepsy, Parkinson's disease, and seizuresor convulsions, sleep disorders, narcolepsy, pain, gastrointestinaldisorders, vestibular dysfunction such as Morbus Meniere, drug abuse andmotion sickness (Timmermann, J. Med. Chem. 1990, 33, 4-11).

There is a need, therefore, to provide for selective, directly acting H3receptor antagonists respectively inverse agonists. Suchantagonists/inverse agonists are useful as therapeutically activesubstances, particularly in the treatment and/or prevention of diseaseswhich are associated with the modulation of H3 receptors.

SUMMARY OF THE INVENTION

In an embodiment of the present invention, provided is a compound offormula I:

wherein:

-   R¹ is selected from the group consisting of lower alkyl, lower    alkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl, lower    hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower    dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted    or substituted with one or two groups independently selected from    lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, lower    phenylalkyl wherein the phenyl ring may be unsubstituted or    substituted with one or two groups independently selected from lower    alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower    heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or    substituted with one or two groups independently selected from lower    alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower    heterocyclyl wherein the heterocyclyl ring may be unsubstituted or    substituted with one or two lower alkyl groups, and lower    heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted    or substituted with one or two lower alkyl groups;-   R² is selected from the group consisting of hydrogen, lower alkyl,    lower alkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl,    lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl,    lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, lower halogenalkoxy and lower    hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may be    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy and lower    hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may    be unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy and lower    hydroxyalkyl, and lower heterocyclyl wherein the heterocyclyl ring    may be unsubstituted or substituted with one or two lower alkyl    groups, and lower heterocyclylalkyl wherein the heterocyclyl ring    may be unsubstituted or substituted with one or two lower alkyl    groups; or-   R¹ and R² together with the nitrogen atom to which they are attached    form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated    heterocyclic ring optionally containing a further heteroatom    selected from nitrogen, oxygen or sulfur, a sulfinyl group or a    sulfonyl group, said saturated or partly unsaturated heterocyclic    ring being unsubstituted or substituted by one, two or three groups    independently selected from lower alkyl, halogen, halogenalkyl,    hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl,    pyridyl and carbamoyl, or being condensed with a phenyl ring, said    phenyl ring being unsubstituted or substituted by one, two or three    groups independently selected from lower alkyl, lower alkoxy and    halogen;-   R³ is selected from the group consisting of hydrogen, lower alkyl,    lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lower    cycloalkylalkyl, lower alkanoyl, lower cyanoalkyl, lower    alkylsulfonyl, phenylsulfonyl wherein the phenyl ring may be    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy, lower    halogenalkoxy and lower hydroxyalkyl, phenyl unsubstituted or    substituted with one or two groups independently selected from lower    alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower    hydroxyalkyl, lower phenylalkyl, wherein the phenyl ring may be    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy, lower    halogenalkoxy and lower hydroxyalkyl, and heteroaryl unsubstituted    or substituted with one or two groups independently selected from    lower alkyl or halogen;-   R⁴ is lower alkyl or cycloalkyl;    and pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, provided is a processfor the manufacture of compounds according to formula I, comprising thesteps of: coupling a compound of formula II

wherein R⁴ is as defined above,with an amine of the formula IIIH—NR¹R²  IIIwherein R¹ and R² are as defined above, under basic conditions to obtaina compound of the formula IA

wherein R³ is hydrogen, and optionally transferring into a compound offormula IB

wherein R³ is a group as defined above other than hydrogen, and ifdesired, converting the compound obtained into a pharmaceuticallyacceptable acid addition salt.

In a further embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to formula I as well as apharmaceutically acceptable carrier and/or adjuvant.

In a yet another embodiment of the present invention, provided is amethod for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors, comprising the step ofadministering a therapeutically active amount of a compound according toformula I to a human being or animal in need thereof.

In a still further embodiment of the present invention, provided is amethod for the treatment or prevention of obesity in a human being oranimal, which method comprises administering a therapeutically effectiveamount of a compound according to formula I in combination orassociation with a therapeutically effective amount of a compoundselected from the group consisting of a lipase inhibitor, an anorecticagent, a selective serotonin reuptake inhibitor, and an agent thatstimulates metabolism of body fat, to said human being or animal in needthereof.

In a yet still another embodiment of the present invention, provided isa method of treatment or prevention of type II diabetes in a human beingor animal, which comprises administering a therapeutically effectiveamount of a compound according to claim 1 in combination or associationwith a therapeutically effective amount of an anti-diabetic agent, tosaid human being or animal in need thereof.

DETAILED DESCRIPTION

In the present description the term “alkyl”, alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated aliphatic hydrocarbon radical of one to twenty carbon atoms,preferably one to sixteen carbon atoms, more preferably one to tencarbon atoms.

The term “lower alkyl” or “C₁-C₈-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, preferably a straight or branched-chain alkyl group with 1to 6 carbon atoms and particularly preferred a straight orbranched-chain alkyl group with 1 to 4 carbon atoms. Examples ofstraight-chain and branched C₁-C₈ alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls,the isomeric hexyls, the isomeric heptyls and the isomeric octyls,preferably methyl and ethyl and most preferred methyl.

The term “lower alkenyl” or “C₂₋₈-alkenyl”, alone or in combination,signifies a straight-chain or branched hydrocarbon radical comprising anolefinic bond and up to 8, preferably up to 6, particularly preferred upto 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.A preferred example is 2-propenyl.

The term “lower alkinyl” or “C₂₋₈-alkinyl”, alone or in combination,signifies a straight-chain or branched hydrocarbon residue comprising atriple bond and up to 8, preferably up to 6, particularly preferred upto 4 carbon atoms. Examples of alkinyl groups are ethinyl, 1-propinyl,or 2-propinyl. A preferred example is 2-propinyl.

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” denotes a saturatedcarbocyclic group containing from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.Especially preferred is cyclopentyl.

The term “lower cycloalkylalkyl” or “C₃₋₇-cycloalkyl-C₁₋₈-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by cycloalkyl. Apreferred example is cyclopropylmethyl.

The term “alkoxy” refers to the group R′—O—, wherein R′ is lower alkyland the term “lower alkyl” has the previously given significance.Examples of lower alkoxy groups are e.g. methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert.-butoxy,preferably methoxy and ethoxy and most preferred methoxy.

The term “lower alkoxyalkyl” or “C₁₋₈-alkoxy-C₁₋₈-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl groups is replaced by an alkoxy group, preferablymethoxy or ethoxy. Among the preferred lower alkoxyalkyl groups are2-methoxyethyl or 3-methoxypropyl.

The term “alkylsulfanyl” or “C₁₋₈-alkylsulfanyl” refers to the groupR′—S—, wherein R′ is lower alkyl and the term “lower alkyl” has thepreviously given significance. Examples of alkylsulfanyl groups are e.g.methylsulfanyl or ethylsulfanyl.

The term “lower alkylsulfanylalkyl” or “C₁₋₈-alkylsulfanyl-C₁₋₈-alkyl”refers to lower alkyl groups as defined above wherein at least one ofthe hydrogen atoms of the lower alkyl groups is replaced by analkylsulfanyl group, preferably methylsulfanyl. An example for apreferred lower alkylsulfanylalkyl group is 2-methylsulfanylethyl.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₈-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Examples oflower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.

The term “dialkylamino” refers to the group —NR′R″, wherein R′ and R″are lower alkyl and the term “lower alkyl” has the previously givensignificance. A preferred dialkylamino group is dimethylamino.

The term “lower dialkylaminoalkyl” or “C₁₋₈-dialkylamino-C₁₋₈-alkyl”refers to lower alkyl groups as defined above wherein at least one ofthe hydrogen atoms of the lower alkyl group is replaced by adialkylamino group, preferably dimethylamino. A preferred lowerdialkylaminoalkyl group is 3-dimethylaminopropyl.

The term “alkylsulfonyl” or “lower alkylsulfonyl” refers to the groupR′—S(O)₂—, wherein R′ is lower alkyl and the term “lower alkyl” has thepreviously given significance. Examples of alkylsulfonyl groups are e.g.methylsulfonyl or ethylsulfonyl.

The term “lower phenylsulfonyl” means the group “phenyl-S(O)₂—”.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “lower halogenalkyl” or “halogen-C₁₋₈-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a halogen atom, preferablyfluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethyl, difluoromethyl,trifluoroethyl, fluoromethyl and chloromethyl, with trifluoromethylbeing especially preferred.

The term “lower halogenalkoxy” or “halogen-C₁₋₈-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom,preferably fluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy,fluoromethoxy and chloromethoxy, with trifluoromethoxy being especiallypreferred.

The term “lower alkanoyl” refers to the group —CO—R′, wherein R′ islower alkyl and the term “lower alkyl” has the previously givensignificance. Preferred is a group —CO—R′, wherein R′ is methyl, meaningan acetyl group.

The term “carbamoyl” refers to the group —CO—NH₂.

The term “dialkylcarbamoyl” refers to the group —CO—NR′R″, wherein R′and R″ are lower alkyl and the term “lower alkyl” has the previouslygiven significance. A preferred dialkylcarbamoyl group isdimethylcarbamoyl.

The term “lower dialkylcarbamoylalkyl” or“C₁₋₈-dialkylcarbamoyl-C₁₋₈-alkyl” refers to lower alkyl groups asdefined above wherein at least one of the hydrogen atoms of the loweralkyl group is replaced by a dialkylcarbamoyl group, preferablydimethylcarbamoyl. A preferred lower dialkylcarbamoylalkyl group is3-dimethylcarbamoylpropyl.

The term “lower phenylalkyl” or “phenyl-C₁₋₈-alkyl” to lower alkylgroups as defined above wherein at least one of the hydrogen atoms ofthe lower alkyl group is replaced by a phenyl group. Preferred lowerphenylalkyl groups are benzyl or phenethyl.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise one, two or three atoms selected from nitrogen, oxygenand/or sulphur. Examples of heteroaryl groups are e.g. furyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl,isothiazolyl, oxazolyl, imidazolyl, or pyrrolyl. Especially preferredare pyridyl, thiazolyl and oxazolyl.

The term “lower heteroarylalkyl” or “heteroaryl-C₁₋₈-alkyl” refers tolower alkyl groups as defined above wherein at least one of the hydrogenatoms of the lower alkyl group is replaced by a heteroaryl group asdefined above.

The term “heterocyclyl” refers to a saturated or partly unsaturated 5-or 6-membered ring which can comprise one, two or three atoms selectedfrom nitrogen, oxygen and/or sulphur. Examples of heterocyclyl ringsinclude piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl,tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, and thiomorpholinyl.A preferred heterocyclyl group is piperidinyl or tetrahydropyranyl.

The term “lower heterocyclylalkyl” or “heterocyclyl-C₁₋₈-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by a heterocyclylgroup as defined above.

The term “form a 4-, 5-, 6- or 7-membered saturated heterocyclic ringoptionally containing a further heteroatom selected from nitrogen,oxygen or sulfur” refers to a saturated N-heterocyclic ring, which mayoptionally contain a further nitrogen, oxygen or sulfur atom, such asazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl. A “4-, 5-, 6- or7-membered partly unsaturated heterocyclic ring” means a heterocyclicring as defined above which contains a double bond, for example 2,5-dihydropyrrolyl or 3,6-dihydro-2H-pyridinyl. A “4-, 5-, 6- or7-membered saturated or partly unsaturated heterocyclic ring containinga sulfinyl group or a sulfonyl group” means a N-heterocyclic ring thatcontains a —S(O)— group or a —SO₂— group, for example1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl. The heterocyclic ringmay be unsubstituted or substituted by one, two or three groupsindependently selected from lower alkyl, lower alkoxy and oxo. Theheterocyclic ring may also be condensed with a phenyl ring, said phenylring being unsubstituted or substituted by one, two or three groupsindependently selected from lower alkyl, lower alkoxy and halogen. Anexample for such a condensed heterocyclic ring is 1,4-dihydro-isoindole.

The term “oxo” means that a C-atom of the heterocyclic ring may besubstituted by ═O, thus meaning that the heterocyclic ring may containone or more carbonyl (—CO—) groups.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared form addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions. Particularly preferred pharmaceuticallyacceptable salts of compounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologicallyacceptable solvates.

“Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

In detail, the present invention relates to compounds of the generalformula

wherein

-   R¹ is selected from the group consisting of lower alkyl, lower    alkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl, lower    hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower    dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted    or substituted with one or two groups independently selected from    lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, lower    phenylalkyl wherein the phenyl ring may be unsubstituted or    substituted with one or two groups independently selected from lower    alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower    heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or    substituted with one or two groups independently selected from lower    alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower    heterocyclyl wherein the heterocyclyl ring may be unsubstituted or    substituted with one or two lower alkyl groups, and lower    heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted    or substituted with one or two lower alkyl groups;-   R² is selected from the group consisting of hydrogen, lower alkyl,    lower alkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl,    lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl,    lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, lower halogenalkoxy and lower    hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may be    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy and lower    hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may    be unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy and lower    hydroxyalkyl, and lower heterocyclyl wherein the heterocyclyl ring    may be unsubstituted or substituted with one or two lower alkyl    groups, and lower heterocyclylalkyl wherein the heterocyclyl ring    may be unsubstituted or substituted with one or two lower alkyl    groups; or-   R¹ and R² together with the nitrogen atom to which they are attached    form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated    heterocyclic ring optionally containing a further heteroatom    selected from nitrogen, oxygen or sulfur, a sulfinyl group or a    sulfonyl group, said saturated or partly unsaturated heterocyclic    ring being unsubstituted or substituted by one, two or three groups    independently selected from lower alkyl, halogen, halogenalkyl,    hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl,    pyridyl and carbamoyl, or being condensed with a phenyl ring, said    phenyl ring being unsubstituted or substituted by one, two or three    groups independently selected from lower alkyl, lower alkoxy and    halogen;-   R³ is selected from the group consisting of hydrogen, lower alkyl,    lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lower    cycloalkylalkyl, lower alkanoyl, lower cyanoalkyl, lower    alkylsulfonyl, phenylsulfonyl wherein the phenyl ring may be    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy, lower    halogenalkoxy and lower hydroxyalkyl, phenyl unsubstituted or    substituted with one or two groups independently selected from lower    alkyl, halogen, lower alkoxy, lower halogenalkoxy and lower    hydroxyalkyl, lower phenylalkyl, wherein the phenyl ring may be    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy, lower    halogenalkoxy and lower hydroxyalkyl, and heteroaryl unsubstituted    or substituted with one or two groups independently selected from    lower alkyl or halogen;-   R⁴ is lower alkyl or cycloalkyl;    and pharmaceutically acceptable salts thereof.

Preferred compounds of formula I of the present invention are compoundsof formula I, wherein

-   R¹ is selected from the group consisting of hydrogen, lower alkyl,    lower alkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl,    lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl,    lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, lower halogenalkoxy and lower    hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may be    unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy and lower    hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may    be unsubstituted or substituted with one or two groups independently    selected from lower alkyl, halogen, lower alkoxy and lower    hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ring may    be unsubstituted or substituted with one or two lower alkyl groups,    and lower heterocyclylalkyl wherein the heterocyclyl ring may be    unsubstituted or substituted with one or two lower alkyl groups;    and R² is hydrogen or lower alkyl.

More preferred are those compounds of formula I, wherein R¹ is selectedfrom the group consisting of lower alkyl, cycloalkyl and lowerheterocyclyl wherein the heterocyclyl ring may be unsubstituted orsubstituted with one or two lower alkyl groups, with those compounds,wherein R¹ is selected from the group consisting of lower alkyl,cycloalkyl and lower heterocyclyl wherein the heterocyclyl ring may beunsubstituted or substituted with one or two lower alkyl groups, andwherein R² is hydrogen or lower alkyl, being especially preferred.

Most preferably, R¹ is selected from the group consisting of ethyl,n-propyl, i-propyl, cyclopentyl, cyclohexyl and tetrahydropyrane.

Furthermore, compounds of formula I according to the present inventionare preferred, wherein R¹ and R² together with the nitrogen atom towhich they are attached form a 4-, 5-, 6- or 7-membered saturated orpartly unsaturated heterocyclic ring optionally containing a furtherheteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group ora sulfonyl group, said saturated or partly unsaturated heterocyclic ringbeing unsubstituted or substituted by one, two or three groupsindependently selected from lower alkyl, halogen, halogenalkyl, hydroxy,lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl andcarbamoyl, or being condensed with a phenyl ring, said phenyl ring beingunsubstituted or substituted by one, two or three groups independentlyselected from lower alkyl, lower alkoxy and halogen.

Within this group, those compounds are preferred, wherein R¹ and R²together with the nitrogen atom to which they are attached form aheterocyclic ring selected from the group consisting of morpholine,piperidine, 2,5-dihydropyrrole, pyrrolidine, azepane, piperazine,azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, said heterocyclicring being unsubstituted or substituted by one, two or three groupsindependently selected from lower alkyl, halogen, halogenalkyl, hydroxy,lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or beingcondensed with a phenyl ring, said phenyl ring being unsubstituted orsubstituted by one, two or three groups independently selected fromlower alkyl, lower alkoxy and halogen.

Especially preferred are those compounds of formula I, wherein R¹ and R²together with the nitrogen atom to which they are attached form aheterocyclic ring selected from the group consisting of pyrrolidine,2,5-dihydropyrrole, morpholine, piperidine, azepane and1,3-dihydroisoindole, wherein said heterocyclic ring is unsubstituted orsubstituted by one, two or three groups independently selected fromlower alkyl, halogen, halogenalkyl, hydroxy, lower alkoxy, oxo, phenyl,benzyl, pyridyl and carbamoyl.

More preferably, R¹ and R² together with the nitrogen atom to which theyare attached form a heterocyclic ring selected from the group consistingof pyrrolidine, 3-hydroxypyrrolidine, 2-iospropyl-pyrrolidine,morpholine, piperidine, 3-methylpiperidine, 2-methylpiperidine,4-methyl-piperidine, 3,5-dimethylpiperidine, 3,3-difluoropiperidine,4,4-difluoropiperidine, 4-methoxypiperidine, 3-hydroxypiperidine,4-trifluoromethyl-piperidine, azepane and 1,3-dihydroisoindole.

Furthermore, compounds of formula I according to the present inventionare preferred, wherein R³ is selected from the group consisting ofhydrogen, lower alkyl, lower halogenalkyl, lower cycloalkylalkyl andlower cyanoalkyl.

Especially preferred are compounds of formula I, wherein R³ is hydrogen.

Further preferred compounds of formula I according to the invention arethose, wherein R⁴ is lower alkyl, with those compounds, wherein R⁴ isisopropyl, being especially preferred.

Also preferred are compounds of formula I according to the presentinvention, wherein R⁴ is cycloalkyl. Especially preferred are thosecompounds of formula I, wherein R⁴ is cyclopentyl.

Examples of preferred compounds of formula I are the following:

-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-pyrrolidin-1-yl-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-morpholin-4-yl-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,-   5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid cyclohexylamide,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-methyl-piperidin-1-yl)-methanone,-   5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid cyclopentylamide,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3,3-difluoro-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-hydroxy-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-trifluoro-methyl-piperidin-1-yl)-methanone,-   5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid propylamide,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-piperidin-1-yl-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-pyrrolidin-1-yl-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-morpholin-4-yl-methanone,-   (1,3-dihydro-isoindol-2-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,-   5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid cyclohexylamide,-   azepan-1-yl-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-methyl-piperidin-1-yl)-methanone,-   5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid cyclopentylamide,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,-   (3-hydroxy-pyrrolidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   (3,3-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,-   (2,5-dihydro-pyrrol-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   (3-hydroxy-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   (3,5-dimethyl-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,-   [5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-trifluoro-methyl-piperidin-1-yl)-methanone,-   5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid propylamide,-   5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid diethylamide,-   5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid (tetrahydro-pyran-4-yl)-amide,    and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I of the present inventionare the following:

-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,-   [5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,-   5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid propylamide,-   (3-hydroxy-pyrrolidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,    and pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutically acceptable salts of the compounds offormula I and the pharmaceutically acceptable esters of the compounds offormula I individually constitute preferred embodiments of the presentinvention.

Compounds of formula I may form acid addition salts with acids, such asconventional pharmaceutically acceptable acids, for examplehydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartarate,and methanesulphonate. Preferred are the hydrochloride salts. Alsosolvates and hydrates of compounds of formula I and their salts formpart of the present invention.

Compounds of formula I can have one or more asymmetric carbon atoms andcan exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluant). The invention embraces all of theseforms.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatized at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined above, which processcomprises coupling a compound of formula II

wherein R⁴ is as defined herein before, with an amine of the formula IIIH—NR¹R²  IIIwherein R¹ and R² are as defined herein before, under basic conditionsto obtain a compound of the formula IA

wherein R³ is hydrogen, and optionally transferring into a compound offormula IB

wherein R³ is a group as defined herein before other than hydrogen, andif desired, converting the compound obtained into a pharmaceuticallyacceptable acid addition salt.

Transferring into a compound of formula IB means treating the compoundof formula IA with a suitable base in a suitable solvent under anhydrousconditions (e.g. sodium hydride in DMF) and reacting the intermediateanion with an alkylating or acylating agent R¹—X, wherein X signifies aleaving group such as e.g. iodide, bromide, methanesulfonate orchloride, to obtain a compound of formula IB wherein R¹ signifies loweralkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lowerhydroxyhalogenalkyl, lower cycloalkylalkyl, lower alkylcarbonyl, loweralkylsulfonyl or phenylsulfonyl.

Typical examples of an alkylating or acylating agent R³—X are methyliodide, benzyl bromide, 2,2,2-trifluoroethyl-methanesulfonate, acetylchloride or benzenesulfonyl chloride.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. The preparation of compounds of formula I of thepresent invention may be carried out in sequential or convergentsynthetic routes. Syntheses of the invention are shown in the followingschemes. The skills required for carrying out the reaction andpurification of the resulting products are known to those skilled in theart. The substituents and indices used in the following description ofthe processes have the significance given herein before unless indicatedto the contrary.

Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

The intermediates of formula II can be prepared following the procedureas depicted in scheme 1.

Compounds of formula II can be prepared according to scheme 1 by aprocess starting from(Z)-3-(2-chloro-5-nitro-pyridin-4-yl)-2-hydroxy-acrylic acid ethyl ester(V). V is formed by aldol condensation from2-chloro-4-methyl-5-nitropyridine (IV) and diethyl oxalate in thepresence of a strong base such as potassium ethoxide, potassiumtert-butylate or preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The coupling of chloro substituted pyridine derivatives with piperazinesis widely described in literature and the procedures are known to thosein the art (For reaction conditions described in literature affectingsuch reactions see for example: Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2nd Edition, Richard C. Larock.John Wiley & Sons, New York, N.Y. 1999).(Z)-3-(2-chloro-5-nitro-pyridin-4-yl)-2-hydroxy-acrylic acid ethyl ester(V) can conveniently be transformed to the respective piperazinylderivatives VII through reaction with a piperazine derivative VI (eithercommercially available or accessible by methods described in referencesor by methods known in the art; as appropriate). The reaction can becarried out in the presence or the absence of a solvent and in thepresence or the absence of a base. We find it convenient to carry outthe reaction in a solvent like water and/or dimethylformamide (DMF) and,if necessary, in the presence of a base like triethylamine ordiisopropyl-ethylamine (DIPEA). There is no particular restriction onthe nature of the solvent to be employed, provided that it has noadverse effect on the reaction or the reagents involved and that it candissolve the reagents, at least to some extent. Examples for suitablesolvents include DMF, dichloromethane (DCM), dioxane, tetrahydrofurane(THF), and the like. The reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. We find it convenient to carry out the reaction withheating from ambient temperature to reflux. The time required for thereaction may also vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents. A period of from0.5 h to several days will usually suffice to yield piperazinyl pyridinederivatives VII.

Compounds of formula II are then obtained from piperazinyl pyridinederivatives VII by a) reaction with iron powder in acetic acid to givethe esters VIII in a temperature range of 70 to 90° C., and b)hydrolization of the esters VIII under basic conditions (e.g. withlithium hydroxide in polar solvents such as e.g. tetrahydrofurane,methanol or water or mixtures thereof). A period of from 12 h to 24 h atroom temperature will usually suffice to yield the carboxylic acids offormula II.

Compounds of the general formula IA and IB can be prepared according toscheme 2. The coupling of carboxylic acids II with amines III (eithercommercially available or accessible by methods described in referencesor by methods known in the art) is widely described in literature (e.g.Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, NewYork, N.Y. 1999) and can be accomplished by employing the usage ofcoupling reagents such as, e.g. N,N-carbonyldiimidazole (CDI),1-hydroxy-1,2,3-benzotriazole (HOBT) orO-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU)in a suitable solvent like, e.g. dimethylformamide (DMF) or dioxane inthe presence of a base (e.g. triethylamine or diisopropylethylamine).

Intermediates of formula IB can be obtained for example throughtreatment of intermediates of formula IA with a suitable base in asuitable solvent under anhydrous conditions (e.g. sodium hydride in DMF)and reacting the intermediate anion with an alkylating or acylatingagent R³—X such as, e.g. methyl iodide, 2-bromopropane,2,2,2-trifluoroethyl-methanesulfonate, methanesulfonyl- orphenylsulfonylchloride. In those cases R³ signifies a methyl,trifluoromethyl, isopropyl or an alkyl- or arylsulfonyl group and Xsignifies a leaving group such as, e.g. iodide, bromide,methanesulfonate or chloride. Compounds of formula IB where R³ signifiesa phenyl or a substituted phenyl group can be synthesized by processesknown to those skilled in the art and described in literature (e.g. W.W. K. R. Mederski et. al, Tetrahedron, 1999, 55, 12757). For example,intermediates of formula IA are reacted with an optionally substitutedphenylboronic acid using an appropriate catalyst (e.g. copper(II)acetate) and base (e.g. pyridine) in a suitable solvent like, e.g.dichloromethane.

As described above, the compounds of formula I of the present inventioncan be used as medicaments for the treatment and/or prevention ofdiseases which are associated with the modulation of H3 receptors.

In this context, the expression ‘diseases associated with the modulationof H3 receptors’ means diseases which can be treated and/or prevented bymodulation of H3 receptors. Such diseases encompass, but are not limitedto, obesity, metabolic syndrome (syndrome X), neurological diseasesincluding Alzheimer's disease, dementia, age-related memory dysfunction,mild cognitive impairment, cognitive deficit, attention deficithyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain,migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness,schizophrenia, depression, addiction, motion sickness and sleepdisorders including narcolepsy, and other diseases including asthma,allergy, allergy-induced airway responses, congestion, chronicobstructive pulmonary disease and gastro-intestinal disorders.

In a preferable aspect, the expression ‘diseases associated withmodulation of H3 receptors’ relates to obesity, metabolic syndrome(syndrome X), and other eating disorders, with obesity being especiallypreferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutically active substances, particularly as therapeutic activesubstances for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are associated with themodulation of H3 receptors, which method comprises administering atherapeutically active amount of a compound of formula I to a humanbeing or animal. A method for the treatment and/or prevention of obesityis preferred.

The invention further relates to the use of compounds of formula I asdefined above for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors.

In addition, the invention relates to the use of compounds of formula Ias defined above for the preparation of medicaments for the treatmentand/or prevention of diseases which are associated with the modulationof H3 receptors. The use of compounds of formula I as defined above forthe preparation of medicaments for the treatment and/or prevention ofobesity is preferred.

Furthermore, the present invention relates to the use of a compound offormula I for the manufacture of a medicament for the treatment andprevention of obesity in a patient who is also receiving treatment witha lipase inhibitor and particularly, wherein the lipase inhibitor isorlistat.

It is a further preferred embodiment of the present invention to providea method for the treatment or prevention of obesity and obesity relateddisorders which comprises administration of a therapeutically effectiveamount of a compound according to formula I in combination orassociation with a therapeutically effective amount of other drugs forthe treatment of obesity or eating disorders so that together they giveeffective relief. Suitable other drugs include, but are not limited to,anorectic agents, lipase inhibitors, selective serotonin reuptakeinhibitors (SSRI) and agents that stimulate metabolism of body fat.Combinations or associations of the above agents may be encompassingseparate, sequential or simultaneous administration.

The term “lipase inhibitor” refers to compounds which are capable ofinhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO 99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to tetrahydrolipstatin.Administration of a therapeutically effective amount of a compoundaccording to formula I in combination or association with atherapeutically effective amount of tetrahydrolipstatin is especiallypreferred.

Tetrahydrolipstatin (orlistat) is a known compound useful for thecontrol or prevention of obesity and hyperlipidemia. See, U.S. Pat. No.4,598,089, issued Jul. 1, 1986, which also discloses processes formaking orlistat and U.S. Pat. No. 6,004,996, which discloses appropriatepharmaceutical compositions. Further suitable pharmaceuticalcompositions are described for example in International PatentApplications WO 00/09122 and WO 00/09123. Additional processes for thepreparation of orlistat are disclosed in European Patent ApplicationsPublication Nos. 0 185 359, 0 189 577, 0 443 449, and 0 524 495.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, APD356, a minorex,amphechloral, amphetamine, axokine, benzphetamine, bupropion,chlorphentermine, clobenzorex, cloforex, clominorex, clortermine,CP945598, cyclexedrine, CYT009-GhrQb, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine, metreleptin,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex, rimonabant, sibutramine,SLV319, SNAP 7941, SR147778 (Surinabant), steroidal plant extract (e.g.P57) and TM30338 and pharmaceutically acceptable salts thereof.

Most preferable anorectic agents are sibutramine, rimonabant andphentermine.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable agents that stimulate metabolism of body fat include, but arenot limited to, growth hormone agonist (e.g. AOD-9604).

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a compound selected from the group consistingof a lipase inhibitor, an anorectic agent, a selective serotoninreuptake inhibitor, and an agent that stimulates metabolism of body fat,is also an embodiment of the present invention.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a lipase inhibitor, preferably withtetrahydrolipstatin, is also an embodiment of the present invention.

It is a further preferred embodiment to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of a lipaseinhibitor, particularly, wherein the lipase inhibitor istetrahydrolipstatin. Also an embodiment of the invention is the methodas described above for the simultaneous, separate or sequentialadministration of a compound according to formula I and a lipaseinhibitor, particularly tetrahydrolipstatin.

It is a further preferred embodiment to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of an anti-diabeticagent.

The term “anti-diabetic agent” refers to compounds selected from thegroup consisting of 1) PPARγ agonists such as pioglitazone (actos) orrosiglitazone (avandia), and the like; 2) biguanides such as metformin(glucophage), and the like; 3) sulfonylureas such as glibenclamide,glimepiride (amaryl), glipizide (glucotrol), glyburide (DiaBeta), andthe like; 4) nonsulfonylureas such as nateglinide (starlix), repaglimide(prandin), and the like; 5) PPARα/γ agonists such as GW-2331, and thelike 6) DPP-IV-inhibitors such as LAF-237 (vildagliptin), MK-0431,BMS-477118 (saxagliptin) or GSK23A and the like; 7) Glucokinaseactivators such as the compounds disclosed in e.g. WO 00/58293 A1, andthe like; 8) α-Glucosidase inhibitors such as acarbose (precose) ormiglitol (glyset), and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of ananti-diabetic agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of Type II diabetes in a patient who isalso receiving treatment with an anti-diabetic agent is also anembodiment of the present invention.

It is a further preferred embodiment to provide a method of treatment orprevention of dyslipidemias in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofa lipid lowering agent.

The term “lipid lowering agent” refers to compounds selected from thegroup consisting of 1) bile acid sequestrants such as cholestyramine(questran), colestipol (colestid), and the like; 2) HMG-CoA reductaseinhibitors such as atorvastatin (lipitor), cerivastatin (baycol),fluvastatin (lescol), pravastatin (pravachol), simvastatin (zocor) andthe like; 3) cholesterol absorption inhibitors such as ezetimibe, andthe like; 4) CETP inhibitors such as torcetrapib, JTT 705, and the like;5) PPARα-agonists such as beclofibrate, gemfibrozil (lopid), fenofibrate(lipidil), bezafibrate (bezalip), and the like; 6) lipoprotein synthesisinhibitors such as niacin, and the like; and 7) niacin receptor agonistssuch as nicotinic acid, and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of a lipidlowering agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of dyslipidemias in a patient who isalso receiving treatment with a lipid lowering agent, is also anembodiment of the present invention.

It is a further preferred embodiment to provide a method of treatment orprevention of hypertension in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofan anti-hypertensive agent.

The term “anti-hypertensive agent” or “blood-pressure lowering agent”refers to compounds selected from the group consisting of 1)Angiotensin-converting Enzyme (ACE) Inhibitors including benazepril(lotensin), captopril (capoten), enalapril (vasotec), fosinopril(monopril), lisinopril (prinivil, zestril), moexipril (univasc),perindopril (coversum), quinapril (accupril), ramipril (altace),trandolapril (mavik), and the like; 2) Angiotensin II ReceptorAntagonists including candesartan (atacand), eprosartan (teveten),irbesartan (avapro), losartan (cozaar), telmisartan (micadisc),valsartan (diovan), and the like; 3) Adrenergic Blockers (peripheral orcentral) such as the beta-adrenergic blockers including acebutolol(sectrol), atenolol (tenormin), betaxolol (kerlone), bisoprolol(zebeta), carteolol (cartrol), metoprolol (lopressor; toprol-XL),nadolol (corgard), penbutolol (levatol), pindolol (visken), propranolol(inderal), timolol (blockadren) and the like; alpha/beta adrenergicblockers including carvedilol (coreg), labetalol (normodyne), and thelike; alpha-1 adrenergic blockers including prazosin (minipress),doxazosin (cardura), terazosin (hytrin), phenoxybenzamine (dibenzyline),and the like; peripheral adrenergic-neuronal blockers includingguanadrel (hylorel), guanethidine (ismelin), reserpine (serpasil), andthe like; alpha-2 adrenergic blockers including a-methyldopa (aldomet),clonidine (catapres), guanabenz (wytensin), guanfacine (tenex), and thelike; 4) Blood Vessel Dilators (Vasodilators) including hydralazine(apresoline), minoxidil (lonitren), clonidine (catapres), and the like;5) Calcium Channel Blockers including amlodipine (norvasc), felodipine(plendil), isradipine (dynacirc), nicardipine (cardine sr), nifedipine(procardia, adalat), nisoldipine (sular), diltiazem (cardizem),verapamil (isoptil), and the like; 6) Diuretics such as thiazides andthiazides-like agents, including hydrochlorothiazide (hydrodiuril,microzide), chlorothiazide (diuril), chlorthalidone (hygroton),indapamide (lozol), metolazone (mykrox), and the like; loop diuretics,such as bumetanide (bumex) and furosemide (lasix), ethacrynic acid(edecrin), torsemide (demadex), and the like; potassium-sparingdiuretics including amiloride (midamor), triamterene (dyrenium),spironolactone (aldactone), and the tiamenidine (symcor) and the like;7) Tyrosine Hydroxylase Inhibitors, including metyrosine (demser), andthe like; 8) Neutral Endopeptidase Inhibitors, including BMS-186716(omapatrilat), UK-79300 (candoxatril), ecadotril (sinorphan), BP-1137(fasidotril), UK-79300 (sampatrilat) and the like; and 9) EndothelinAntagonists including tezosentan (RO0610612), A308165, and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of aanti-hypertensive agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of hypertension in a patient who isalso receiving treatment with an anti-hypertensive agent, is also anembodiment of the present invention.

As described above, the compounds of formula I and theirpharmaceutically acceptable salts possess valuable pharmacologicalproperties. Specifically, it has been found that the compounds of thepresent invention are good histamine 3 receptor (H3R) antagonists and/orinverse agonists.

The following test was carried out in order to determine the activity ofthe compounds of formula (I).

Binding Assay with ³H-(R)α-methylhistamine

Saturation binding experiments were performed using HR3-CHO membranesprepared as described in Takahashi, K, Tokita, S., Kotani, H. (2003) J.Pharmacol. Exp. Therapeutics 307, 213-218.

An appropriate amount of membrane (60 to 80 μg protein/well) wasincubated with increasing concentrations of ³H(R)α-Methylhistaminedi-hydrochloride (0.10 to 10 nM). Non specific binding was determinedusing a 200 fold excess of cold (R)α-Methylhistamine dihydrobromide (500nM final concentration). The incubation was carried out at roomtemperature (in deep-well plates shaking for three hours). The finalvolume in each well was 250 μl. The incubation was followed by rapidfiltration on GF/B filters (pre-soaked with 100 μl of 0.5% PEI in Tris50 mM shaking at 200 rpm for two hours). The filtration was made using acell-harvester and the filter plates were then washed five times withice cold washing buffer containing 0.5 M NaCl. After harvesting, theplates were dried at 55° C. for 60 min, then we added scintillationfluid (Microscint 40, 40 microl in each well) and the amount ofradioactivity on the filter was determined in Packard top-counter aftershaking the plates for two hours at 200 rpm at room temperature.

Binding Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂x6H₂O pH 7.4.Washing Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂x6H₂O and 0.5 M NaClpH 7.4.

Indirect measurement of affinity of H3R inverse agonists: twelveincreasing concentrations (ranging from 10 μM to 0.3 nM) of the selectedcompounds were always tested in competition binding experiments usingmembrane of the human HR3-CHO cell line. An appropriate amount ofprotein, e.g. approximately 500 cpm binding of RAMH at Kd, wereincubated for 1 hour at room temperature in 250 μl final volume in96-well plates in presence of ³H(R)α-Methylhistamine (1 nM finalconcentration=Kd). Non-specific binding was determined using a 200 foldexcess of cold (R)α-Methylhistamine dihydrobromide.

All compounds were tested at a single concentration in duplicates.Compounds that showed an inhibition of [³H]-RAMH by more than 50% weretested again to determine IC₅₀ in a serial dilution experiment. Ki'swere calculated from IC₅₀ based on Cheng-Prusoff equation (Cheng, Y,Prusoff, W H (1973) Biochem Pharmacol 22, 3099-3108).

The compounds of the present invention exhibit K_(i) values within therange of about 1 nM to about 1000 nM, preferably of about 1 nM to about100 nM, and more preferably of about 1 nM to about 30 nM. The followingtable shows measured values for some selected compounds of the presentinvention.

K_(i) (nM) Example 1 33 Example 13 27.4 Example 27 63.1

Demonstration of additional biological activities of the compounds ofthe present invention may be accomplished through in vitro, ex vivo, andin vivo assays that are well known in the art. For example, todemonstrate the efficacy of a pharmaceutical agent for the treatment ofobesity-related disorders such as diabetes, Syndrome X, oratherosclerotic disease and related disorders such ashypertriglyceridemia and hypercholesteremia, the following assays may beused.

Method for Measuring Blood Glucose Levels

db/db mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean blood glucose levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. At this point, the animals are bled again by eye ortail vein and blood glucose levels are determined.

Method for Measuring Triglyceride Levels

hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean serum triglyceride levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. The animals are then bled again by eye or tail vein,and serum triglyceride levels are determined.

Method for Measuring HDL-Cholesterol Levels

To determine plasma HDL-cholesterol levels, hApoAl mice are bled andgrouped with equivalent mean plasma HDL-cholesterol levels. The mice areorally dosed once daily with vehicle or test compound for 7 to 14 days,and then bled on the following day. Plasma is analyzed forHDL-cholesterol.

The compounds of formula (I) and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula (I) and theirpharmaceutically acceptable, into a galenical administration formtogether with suitable, non-toxic, inert, therapeutically compatiblesolid or liquid carrier materials and, if desired, usual pharmaceuticaladjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavor-improving agents, salts for varyingthe osmotic pressure, buffer substances, solubilizers, colorants andmasking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg,preferably 0.5-100 mg, of a compound of formula (I).

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Example 1[5-(4-Cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-pyrrolidin-1-yl-methanoneStep 1: (Z)-3-(2-Chloro-5-nitro-pyridin-4-yl)-2-hydroxy-acrylic acidethyl ester

A mixture of 1.5 g (8.7 mmol) 2-chloro-4-methyl-5-nitropyridine(commercially available) in 5.88 mL (43.5 mmol) diethyl oxalate wastreated with 2.34 ml (15.6 mmol) 1,8-diazabicylo[5.4.0]undec-7-ene andstirred for 4 h at room temperature. After evaporation of all volatilesthe residue was acidified with 1N KHSO₄ aq. and extracted with DCM. Thecombined organic layers were dried with MgSO₄ and concentrated underreduced pressure to afford 3.16 g of the title compounds which was usedwithout further purification in the next step.

MS (m/e): 273.0 (MH⁺; 100%).

Step 2:(Z)-3-[2-(4-Cyclopentyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-2-hydroxy-acrylicacid ethyl ester

A mixture of 3.16 g(Z)-3-(2-chloro-5-nitro-pyridin-4-yl)-2-hydroxy-acrylic acid ethyl esterin 40 mL DMF was treated with 2.96 g (192 mmol) 1-cyclopentyl-piperazineand heated to 110° C. for 1.5 h. The mixture was diluted with 1N NaHCO₃aq. and extracted with DCM. The combined organic layers were dried withMgSO₄ and evaporated to dryness to yield the title compound which wasused without further purification.

MS (m/e): 391.1 (MH⁺; 100%).

Step 3:5-(4-Cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid ethyl ester

(Z)-3-[2-(4-Cyclopentyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-2-hydroxy-acrylicacid ethyl ester was reacted with 0.47 g iron powder in 40 mL aceticacid for 6 h at 80° C. After evaporation of all volatiles the residuewas taken up in water and extracted with DCM. The combined organiclayers were dried with MgSO₄ and evaporated to dryness. Purification onsilica eluting with a gradient mixture of n-heptan/ethyl acetate/0.1%NEt₃ yielded after evaporation of the product fractions 0.65 g (23% from2-chloro-4-methyl-5-nitropyridine) of the title compound as light brownsolid.

MS (m/e): 343.1 (MH⁺; 100%).

Step 4:5-(4-Cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid (Intermediate 1)

A mixture of 0.65 g (1.9 mmol)5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid ethyl ester and LiOHxH₂O in THF/methanol/water was stirred at roomtemperature for 16 h. After evaporation of all volatiles the residue wastaken up in water and HCl conc. was added. After evaporation the residuewas treated with diethyl ether filtered, washed again with diethyl etherand dried to yield 0.46 g (69%) of the title compound as orange solid.

MS (m/e): 315.4 (MH⁺; 100%).

Step 5:[5-(4-Cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-pyrrolidin-1-yl-methanone

A mixture of 0.46 g (1.31 mmol)5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid 0.56 mL (6.6 mmol) oxalylchloride and 0.03 mL DMF in 30 mL DCM wasstirred at room temperature for 1 h and evaporated to dryness. Analiquot containing 0.054 mmol of the intermediately built acid chloridewas treated with 27 mg (0.27 mmol) triethylamine and 11.6 mg (0.16 mmol)pyrrolidine in 2 mL DCM during 16 h at room temperature. Afterevaporation of all volatiles the residue was taken up in a mixture ofDMF/methanol/water/NEt₃ and subjected to preparative HPLC purificationon reversed phase eluting with a acetonitrile/water (0.05% NEt₃)gradient. After evaporation of the product fractions 4.1 mg (14%) of thetitle compound was obtained.

MS (m/e): 368.3 (MH⁺; 100%)

Intermediate 25-(4-Isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid Step 1:(Z)-2-Hydroxy-3-[2-(4-isopropyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-acrylicacid ethyl ester

According to the procedure described for the synthesis of Example 1,Step 2((Z)-3-[2-(4-cyclopentyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-2-hydroxy-acrylicacid ethyl ester) the title compound was synthesized from2-chloro-4-methyl-5-nitropyridine and isopropyl-piperazine and usedafter isolation without further purification.

MS (m/e): 365.0 (MH⁺; 100%)

Step 2:5-(4-Isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid ethyl ester

According to the procedure described for the synthesis of Example 1,Step 3(5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid ethyl ester) the title compound was synthesized from(Z)-2-hydroxy-3-[2-(4-isopropyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-acrylicacid ethyl ester and used after isolation without further purification.

MS (m/e): 317.3 (MH⁺; 100%)

Step 3:5-(4-Isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid (Intermediate 2)

According to the procedure described for the synthesis of Example 1;Step 4(5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid (intermediate 1)) was synthesized from5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid ethyl ester and used after isolation without further purification.

MS (m/e): 289.0 (MH⁺; 100%)

According to the procedure described for the synthesis of Example 1further 5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine derivatives havebeen synthesized from the respective intermediate mentioned in Table 1and the respective amine mentioned in Table 1. The examples are compiledin Table 1 and comprise Example 2 to Example 36.

MW MH⁺ Ex. No. Name MW Starting materials found 2 [5-(4-cyclopentyl-383.5 5-(4-cyclopentyl-piperazin-1-yl)- 384.4 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 1) 2-yl]-morpholin-4-yl- and methanone morpholine(commercially available) 3 [5-(4-cyclopentyl- 395.65-(4-cyclopentyl-piperazin-1-yl)- 396.4 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 1) 2-yl]-(3-methyl- and piperidin-1-yl)-3-methyl-piperidine methanone (commercially available) 45-(4-cyclopentyl- 395.6 5-(4-cyclopentyl-piperazin-1-yl)- 396.4piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridine-carboxylic acid (Intermediate 1) 2-carboxylic acid and cyclohexylamidecyclohexylamine (commercially available) 5 [5-(4-cyclopentyl- 395.65-(4-cyclopentyl-piperazin-1-yl)- 396.4 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 1) 2-yl]-(2-methyl- and piperidin-1-yl)-2-methyl-piperidine methanone (commercially available) 65-(4-cyclopentyl- 381.5 5-(4-cyclopentyl-piperazin-1-yl)- 382.4piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridine-carboxylic acid (Intermediate 1) 2-carboxylic acid and cyclopentylaminecyclopentylamide (commercially available) 7 [5-(4-cyclopentyl- 395.65-(4-cyclopentyl-piperazin-1-yl)- 396.4 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 1) 2-yl]-(4-methyl- and piperidin-1-yl)-4-methyl-piperidine methanone (commercially available) 8[5-(4-cyclopentyl- 383.5 5-(4-cyclopentyl-piperazin-1-yl)- 384.4piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin-carboxylic acid (Intermediate 1) 2-yl]-(3-hydroxy- and pyrrolidin-1-yl)-3-hydroxy-pyrrolidine methanone (commercially available) 9[5-(4-cyclopentyl- 417.5 5-(4-cyclopentyl-piperazin-1-yl)- 418.3piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin-carboxylic acid (Intermediate 1) 2-yl]-(3,3-difluoro- andpiperidin-1-yl)- 3,3-di-fluoro-piperidine methanone (commerciallyavailable) 10 [5-(4-cyclopentyl- 411.5 5-(4-cyclopentyl-piperazin-1-yl)-412.4 piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2-pyrrolo[2,3-c]pyridin- carboxylic acid (Intermediate 1)2-yl]-(4-methoxy- and piperidin-1-yl)- 4-methoxy-piperidine methanone(commercially available) 11 [5-(4-cyclopentyl- 397.55-(4-cyclopentyl-piperazin-1-yl)- 398.3 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 1) 2-yl]-(3-hydroxy- and piperidin-1-yl)-3-hydoxy-piperidine methanone (commercially available) 12[5-(4-cyclopentyl- 449.5 5-(4-cyclopentyl-piperazin-1-yl)- 450.3piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin-carboxylic acid (Intermediate 1) 2-yl]-(4-trifluoromethyl- andpiperidin-1-yl)- 4-trifluoromethyl-piperidine methanone (commerciallyavailable) 13 5-(4-cyclopentyl- 355.5 5-(4-cyclopentyl-piperazin-1-yl)-356.3 piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2-pyrrolo[2,3-c]pyridine- carboxylic acid (Intermediate 1) 2-carboxylicacid and propylamide propylamine (commercially available) 14[5-(4-cyclopentyl- 409.6 5-(4-cyclopentyl-piperazin-1-yl)- 410.4piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin-carboxylic acid (Intermediate 1) 2-yl]-(2-isopropyl- andpyrrolidin-1-yl)- 2-isopropyl-pyrrolidine methanone (commerciallyavailable) 15 [5-(4-isopropyl- 355.5 5-(4-isopropyl-piperazin-1-yl)-356.3 piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2-pyrrolo[2,3-c]pyridin- carboxylic acid (Intermediate 2)2-yl]-piperidin-1-yl- and methanone piperidine (commercially available)16 [5-(4-isopropyl- 341.5 5-(4-isopropyl-piperazin-1-yl)- 342.3piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin-carboxylic acid (Intermediate 2) 2-yl]-pyrrolidin-1-yl- and methanonepyrrolidine (commercially available) 17 [5-(4-isopropyl- 357.55-(4-isopropyl-piperazin-1-yl)- 358.4 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 2) 2-yl]-morpholin-4-yl- and methanone morpholine(commercially available) 18 (1,3-dihydro-isoindol- 389.55-(4-isopropyl-piperazin-1-yl)- 390.4 2-yl)-[5-(4-isopropyl-1H-pyrrolo[2,3-c]pyridine-2- piperazin-1-yl)-1H- carboxylic acid(Intermediate 2) pyrrolo[2,3-c]pyridin- and 2-yl]-methanone2,3-dihydro-1H-isoindole (commercially available) 19 [5-(4-isopropyl-369.5 5-(4-isopropyl-piperazin-1-yl)- 370.3 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 2) 2-yl]-(3-methyl- and piperidin-1-yl)-3-methyl-piperidine methanone (commercially available) 205-(4-isopropyl- 369.5 5-(4-isopropyl-piperazin-1-yl)- 370.3piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridine-carboxylic acid (Intermediate 2) 2-carboxylic acid and cyclohexylamidecyclohexylamine (commercially available) 21 azepan-1-yl-[5-(4- 369.55-(4-isopropyl-piperazin-1-yl)- 370.3 isopropyl-piperazin-1-1H-pyrrolo[2,3-c]pyridine-2- yl)-1H-pyrrolo[2,3- carboxylic acid(Intermediate 2) c]pyridin-2-yl]- and methanone azepine (commerciallyavailable) 22 [5-(4-isopropyl- 369.5 5-(4-isopropyl-piperazin-1-yl)-370.3 piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2-pyrrolo[2,3-c]pyridin- carboxylic acid (Intermediate 2) 2-yl]-(2-methyl-and piperidin-1-yl)- 2-methyl-piperidine methanone (commerciallyavailable) 23 5-(4-isopropyl- 355.5 5-(4-isopropyl-piperazin-1-yl)-356.3 piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2-pyrrolo[2,3-c]pyridine- carboxylic acid (Intermediate 2) 2-carboxylicacid and cyclopentylamide cyclopentylamine (commercially available) 24[5-(4-isopropyl- 383.5 5-(4-isopropyl-piperazin-1-yl)- 384.4piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin-carboxylic acid (Intermediate 2) 2-yl]-(2-isopropyl- andpyrrolidin-1-yl)- 2-isopropyl-pyrrolidine methanone (commerciallyavailable) 25 [5-(4-isopropyl- 369.5 5-(4-isopropyl-piperazin-1-yl)-370.3 piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2-pyrrolo[2,3-c]pyridin- carboxylic acid (Intermediate 2) 2-yl]-(4-methyl-and piperidin-1-yl)- 4-methyl-piperidine methanone (commerciallyavailable) 26 (3-hydroxy-pyrrolidin- 357.55-(4-isopropyl-piperazin-1-yl)- 358.5 1-yl)-[5-(4-isopropyl-1H-pyrrolo[2,3-c]pyridine-2- piperazin-1-yl)-1H- carboxylic acid(Intermediate 2) pyrrolo[2,3-c]pyridin- and 2-yl]-methanone3-hydroxy-pyrrolidine (commercially available) 27(4,4-difluoro-piperidin- 391.5 5-(4-isopropyl-piperazin-1-yl)- 392.21-yl)-[5-(4-isopropyl- 1H-pyrrolo[2,3-c]pyridine-2- piperazin-1-yl)-1H-carboxylic acid (Intermediate 2) pyrrolo[2,3-c]pyridin- and2-yl]-methanone 4,4-difluoro-piperidine (commercially available) 28(3,3-difluoro-piperidin- 391.5 5-(4-isopropyl-piperazin-1-yl)- 392.21-yl)-[5-(4-isopropyl- 1H-pyrrolo[2,3-c]pyridine-2- piperazin-1-yl)-1H-carboxylic acid (Intermediate 2) pyrrolo[2,3-c]pyridin- and2-yl]-methanone 3,3-difluoro-piperidine (commercially available) 29[5-(4-isopropyl- 385.5 5-(4-isopropyl-piperazin-1-yl)- 386.3piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin-carboxylic acid (Intermediate 2) 2-yl]-(4-methoxy- and piperidin-1-yl)-4-methoxy-piperidine methanone (commercially available) 30(2,5-dihydro-pyrrol-1- 339.4 5-(4-isopropyl-piperazin-1-yl)- 340.2yl)-[5-(4-isopropyl- 1H-pyrrolo[2,3-c]pyridine-2- piperazin-1-yl)-1H-carboxylic acid (Intermediate 2) pyrrolo[2,3-c]pyridin- and2-yl]-methanone 2,5-dihydro-1H-pyrrole (commercially available) 31(3-hydroxy-piperidin- 371.5 5-(4-isopropyl-piperazin-1-yl)- 372.31-yl)-[5-(4-isopropyl- 1H-pyrrolo[2,3-c]pyridine-2- piperazin-1-yl)-1H-carboxylic acid (Intermediate 2) pyrrolo[2,3-c]pyridin- and2-yl]-methanone 3-hydroxy-piperidine (commercially available) 32(3,5-dimethyl- 383.5 5-(4-isopropyl-piperazin-1-yl)- 384.3piperidin-1-yl)-[5-(4- 1H-pyrrolo[2,3-c]pyridine-2-isopropyl-piperazin-1- carboxylic acid (Intermediate 2)yl)-1H-pyrrolo[2,3- and c]pyridin-2-yl]- 3,5-dimethyl-piperidinemethanone (commercially available) 33 [5-(4-isopropyl- 423.55-(4-isopropyl-piperazin-1-yl)- 424.3 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridin- carboxylic acid(Intermediate 2) 2-yl]-(4-trifluoromethyl- and piperidin-1-yl)-4-trifluoromethyl-piperidine methanone (commercially available) 345-(4-isopropyl- 329.4 5-(4-isopropyl-piperazin-1-yl)- 330.3piperazin-1-yl)-1H- 1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridine-carboxylic acid (Intermediate 2) 2-carboxylic acid and propylamidepropylamine (commercially available) 35 5-(4-isopropyl- 343.55-(4-isopropyl-piperazin-1-yl)- 344.3 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridine- carboxylic acid(Intermediate 2) 2-carboxylic acid and diethylamide diethylamine(commercially available) 36 5-(4-isopropyl- 371.55-(4-isopropyl-piperazin-1-yl)- 372.3 piperazin-1-yl)-1H-1H-pyrrolo[2,3-c]pyridine-2- pyrrolo[2,3-c]pyridine- carboxylic acid(Intermediate 2) 2-carboxylic acid and (tetrahydro-pyran-4-tetrahydro-pyran-4-ylamine yl)-amide (commercially available)

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg  200.0mg  Microcrystalline cellulose 23.5 mg  43.5 mg  Lactose hydrous 60.0mg  70.0 mg  Povidone K30 12.5 mg  15.0 mg  Sodium starch glycolate 12.5mg  17.0 mg  Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg  Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mgPolyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide(yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesiumstearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavoring additives and filled into sachets.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of formula I:

wherein: R¹ is selected from the group consisting of lower alkyl, loweralkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl, lowerhydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lowerdialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted orsubstituted with one or two groups independently selected from loweralkyl, lower halogenalkoxy and lower hydroxyalkyl, lower phenylalkylwherein the phenyl ring may be unsubstituted or substituted with one ortwo groups independently selected from lower alkyl, halogen, loweralkoxy and lower hydroxyalkyl, lower heteroarylalkyl wherein theheteroaryl ring may be unsubstituted or substituted with one or twogroups independently selected from lower alkyl, halogen, lower alkoxyand lower hydroxyalkyl, lower heterocyclyl wherein the heterocyclyl ringmay be unsubstituted or substituted with one or two lower alkyl groups,and lower heterocyclylalkyl wherein the heterocyclyl ring may beunsubstituted or substituted with one or two lower alkyl groups; R² isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkinyl, cycloalkyl, lower cycloalkylalkyl, lowerhydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lowerdialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted orsubstituted with one or two groups independently selected from loweralkyl, lower halogenalkoxy and lower hydroxyalkyl, lower phenylalkylwherein the phenyl ring may be unsubstituted or substituted with one ortwo groups independently selected from lower alkyl, halogen, loweralkoxy and lower hydroxyalkyl, lower heteroarylalkyl wherein theheteroaryl ring may be unsubstituted or substituted with one or twogroups independently selected from lower alkyl, halogen, lower alkoxyand lower hydroxyalkyl, and lower heterocyclyl wherein the heterocyclylring may be unsubstituted or substituted with one or two lower alkylgroups, and lower heterocyclylalkyl wherein the heterocyclyl ring may beunsubstituted or substituted with one or two lower alkyl groups; or R¹and R² together with the nitrogen atom to which they are attached form a4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclicring optionally containing a further heteroatom selected from nitrogen,oxygen or sulfur, a sulfinyl group or a sulfonyl group, said saturatedor partly unsaturated heterocyclic ring being unsubstituted orsubstituted by one, two or three groups independently selected fromlower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, loweralkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensedwith a phenyl ring, said phenyl ring being unsubstituted or substitutedby one, two or three groups independently selected from lower alkyl,lower alkoxy and halogen; R³ is selected from the group consisting ofhydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lowerhalogenalkyl, lower cycloalkylalkyl, lower alkanoyl, lower cyanoalkyl,lower alkylsulfonyl, phenylsulfonyl wherein the phenyl ring may beunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, halogen, lower alkoxy, lower halogenalkoxyand lower hydroxyalkyl, phenyl unsubstituted or substituted with one ortwo groups independently selected from lower alkyl, halogen, loweralkoxy, lower halogenalkoxy and lower hydroxyalkyl, lower phenylalkyl,wherein the phenyl ring may be unsubstituted or substituted with one ortwo groups independently selected from lower alkyl, halogen, loweralkoxy, lower halogenalkoxy and lower hydroxyalkyl, and heteroarylunsubstituted or substituted with one or two groups independentlyselected from lower alkyl or halogen; R⁴ is lower alkyl or cycloalkyl;and pharmaceutically acceptable salts thereof.
 2. The compound accordingto claim 1, wherein R¹ is selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl, lowercycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, loweralkylsulfanylalkyl, lower dialkylaminoalkyl, lowerdialkylcarbamoylalkyl, phenyl unsubstituted or substituted with one ortwo groups independently selected from lower alkyl, lower halogenalkoxyand lower hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may beunsubstituted or substituted with one or two groups independentlyselected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,lower heteroarylalkyl wherein the heteroaryl ring may be unsubstitutedor substituted with one or two groups independently selected from loweralkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heterocyclylwherein the heterocyclyl ring may be unsubstituted or substituted withone or two lower alkyl groups, and lower heterocyclylalkyl wherein theheterocyclyl ring may be unsubstituted or substituted with one or twolower alkyl groups; and R² is hydrogen or lower alkyl.
 3. The compoundaccording to claim 1, wherein R¹ is selected from the group consistingof lower alkyl, cycloalkyl and lower heterocyclyl wherein theheterocyclyl ring may be unsubstituted or substituted with one or twolower alkyl groups.
 4. The compound according to claim 1, wherein R¹ andR² together with the nitrogen atom to which they are attached form a 4-,5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ringoptionally containing a further heteroatom selected from nitrogen,oxygen or sulfur, a sulfinyl group or a sulfonyl group, said saturatedor partly unsaturated heterocyclic ring being unsubstituted orsubstituted by one, two or three groups independently selected fromlower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, loweralkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensedwith a phenyl ring, said phenyl ring being unsubstituted or substitutedby one, two or three groups independently selected from lower alkyl,lower alkoxy and halogen.
 5. The compound according to claim 1, whereinR¹ and R² together with the nitrogen atom to which they are attachedform a heterocyclic ring selected from the group consisting ofmorpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine, azepane,piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, saidheterocyclic ring being unsubstituted or substituted by one, two orthree groups independently selected from lower alkyl, halogen,halogenalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl andcarbamoyl, or being condensed with a phenyl ring, said phenyl ring beingunsubstituted or substituted by one, two or three groups independentlyselected from lower alkyl, lower alkoxy and halogen.
 6. The compoundaccording to claim 1, wherein R¹ and R² together with the nitrogen atomto which they are attached form a heterocyclic ring selected from thegroup consisting of pyrrolidine, 2,5-dihydropyrrole, morpholine,piperidine, azepane and 1,3-dihydroisoindole, wherein said heterocyclicring is unsubstituted or substituted by one, two or three groupsindependently selected from lower alkyl, halogen, halogenalkyl, hydroxy,lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl.
 7. Thecompound according to claim 1, wherein R¹ and R² together with thenitrogen atom to which they are attached form a heterocyclic ringselected from the group consisting of pyrrolidine, 3-hydroxypyrrolidine,2-iospropyl-pyrrolidine, morpholine, piperidine, 3-methylpiperidine,2-methylpiperidine, 4-methyl-piperidine, 3,5-dimethylpiperidine,3,3-difluoropiperidine, 4,4-difluoropiperidine, 4-methoxypiperidine,3-hydroxypiperidine, 4-trifluoromethylpiperidine, azepane and1,3-dihydroisoindole.
 8. The compound according to claim 1, wherein R³is hydrogen.
 9. The compound according to claim 1, wherein R⁴ is loweralkyl.
 10. The compound according to claim 1, wherein R⁴ is isopropyl.11. The compound according to claim 1, wherein R⁴ is cycloalkyl.
 12. Thecompound according to claim 1, wherein R⁴ is cyclopentyl.
 13. Thecompound according to claim 1, selected from the group consisting of[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-pyrrolidin-1-yl-methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-morpholin-4-yl-methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid cyclohexylamide,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-methyl-piperidin-1-yl)-methanone,5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid cyclopentylamide,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3,3-difluoro-piperidin-1-yl)methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-hydroxy-piperidin-1-yl)-methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-trifluoro-methyl-piperidin-1-yl)-methanone,5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid propylamide,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-piperidin-1-yl-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-pyrrolidin-1-yl-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-morpholin-4-yl-methanone,(1,3-dihydro-isoindol-2-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid cyclohexylamide,azepan-1-yl-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-methyl-piperidin-1-yl)-methanone,5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid cyclopentylamide,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(2-isopropyl-pyrrolidin-1-yl)-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,(3-hydroxy-pyrrolidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,(4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,(3,3-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,(2,5-dihydro-pyrrol-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,(3-hydroxy-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,(3,5-dimethyl-piperidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-methanone,[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-trifluoro-methyl-piperidin-1-yl)-methanone,5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid propylamide,5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid diethylamide,5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid (tetrahydro-pyran-4-yl)-amide, and pharmaceutically acceptablesalts thereof.
 14. The compound according to claim 1, selected from thegroup consisting of[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,[5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid propylamide,(3-hydroxy-pyrrolidin-1-yl)-[5-(4-isopropyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2yl]-methanone,and pharmaceutically acceptable salts thereof.
 15. A process for themanufacture of compounds according to claim 1, comprising the steps of:coupling a compound of formula II

 wherein R⁴ is as defined in claim 1, with an amine of the formula IIIH—NR¹R²  III  wherein R¹ and R² are as defined in claim 1, under basicconditions to obtain a compound of the formula IA

 wherein R³ is hydrogen, and optionally transferring into a compound offormula IB

 wherein R³ is a group as defined in claim 1 other than hydrogen, and ifdesired, converting the compound obtained into a pharmaceuticallyacceptable acid addition salt.
 16. A pharmaceutical composition,comprising a therapeutically effective amount of a compound according toclaim 1 as well as a pharmaceutically acceptable carrier and/oradjuvant.